It was recently discovered that arisugacin, a natural product isolated from a culture of Penicillium, is an inhibitor of acetylcholinesterase (AChE), and on this basis arisugacin has been predicted to be effective in the treatment of Alzheimer's disease. Related compounds also showed inhibitory activity. Omura, S., et al. (1995), "Arisugacin, a Novel and Selective Inhibitor of Acetylcholinesterase from Penicillium sp. FO-4259," J. Antibiotics 48:745-746. Arisugacin and the related compounds are tetracyclic pyrones (having four fused rings). Other tetracyclic pyrones, certain pyripyropenes, have been shown to be inhibitors of cholesterol acyltransferase (ACAT), and therefore have been predicted to be effective in the treatment of atherosclerosis and hypercholesterolemia. Omura, S., et al. (1993), "Pyripyropenes, Highly Potent Inhibitors of Acyl-CoA; Cholesterol Acyltransferase Produced by Aspergillus fumigatus," J. Antibiotics 46:1168-1169; and "Kim, Y. K. et al. (1994), "Pyripyropenes, Novel Inhibitors of Acyl-CoA:Cholesterol Acyltransferase Produced by Aspergillus fumigatus," J. Antibiotics 47:154-162. Pyripyropene A, one such inhibitor, is further characterized in Tomoda, H., et al. (1994), "Relative and Absolute Stereochemistry of Pyripyropene A, A Potent, Bioavailable Inhibitor of Acyl-CoA:Cholesterol Acyltransferase (ACAT)," J. Am. Chem. Soc. 116:12097-12098.
A number of multicyclic pyrones are known to the art and described in Chemical Abstracts; however, tricyclic and tetracycic pyrones as disclosed and claimed herein, appear not to have been previously described.
There is a need for simpler inhibitors of AchE and ACAT that are useful as treatments for Alzheimer's disease, atherosclerosis and hypercholesterolemia.